The development of an HIV-1 vaccine that elicits durable and broadly reactive functional antibodies remains an unsolved problem. While non-neutralizing antibodies that mediate antibody-dependent cellular cytotoxicity (ADCC) are more readily induced by current vaccine strategies, these vaccines have not provided long-term protection. Vaccines that elicit broadly neutralizing antibodies (bnAbs) have been a goal for the field, but known bnAbs share characteristics that make them less likely to be elicited by vaccines. Recent work has suggested bnAbs may be selectively elicited through the use of B cell lineage immunogen design?eg, by harnessing bnAb maturation pathways derived from HIV-1 infected patients. However, in patients that do make bnAbs, it has been shown that bnAbs rarely arise before ~2.5 years after infection, suggesting that persistent antigen drive may be required to drive bnAb development. Thus, vaccine strategies that provide persistent antigenic stimulation using carefully selected immunogens may be able to drive the development of bnAbs and improve the durability of ADCC-mediating antibodies that could provide protection from infection. The question to be addressed by this project is whether persistent antigen stimulation by integrase-defective lentiviral vectors (IDLVs) engineered to sequentially express CH505 T/F envelope and a series of variants assoicated with broad CD4 binding site neutralizing antibodies can elicit antibodies with functional activities against HIV-1, including bnAbs and non-neutralizing antibodies (V1V2, ADCC). A viral challenge will determine if this strategy can provide protection. We hypothesize that persistent antigenic stimulation combined with B-cell lineage immunogen design will promote antibody maturation leading to the development of characteristics shared by known bnAbs and will result in the persistence of B cell clonal lineages over time. AIM.1?Determine functional plasma antibody activity elicited by IDLVs expressing CH505 Envs. AIM.2?Determine the degree of B cell maturation and clonal expansion elicited by IDLVs expressing CH505 Envs. AIM.3?Determine the degree of Tfh response elicited by IDLVs expressing CH505 Envs.